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PD-1 阻断可逆转新冠后免疫异常,并刺激抗 SARS-CoV-2 免疫反应。

PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response.

机构信息

International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy.

Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

出版信息

JCI Insight. 2021 Dec 22;6(24):e146701. doi: 10.1172/jci.insight.146701.

Abstract

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.

摘要

相当大比例的新冠肺炎(COVID-19)患者在出院后数月仍会出现与 COVID-19 相关的症状。我们对从 COVID-19 中康复的患者进行了广泛的免疫学特征分析。与健康对照组相比,这些患者的 T 细胞耗竭,PD-1+T 细胞增加。新冠肺炎患者的白细胞介素 1β(IL-1β)、白细胞介素 1 受体拮抗剂(IL-1RA)和白细胞介素 8(IL-8)等多种细胞因子的血浆水平也升高。从 COVID-19 中康复的患者的体外 T 细胞反应对非特异性和特异性刺激均减弱,揭示了 T 细胞功能障碍状态,包括对 SARS-CoV-2 抗原的反应不良。还观察到 CD8+T 细胞中血浆可溶性 PD-L1 以及 PD1 启动子甲基化和 PD1 靶向 miR-15-5p 的水平改变,表明 PD-1/PD-L1 免疫检查点轴的功能异常。值得注意的是,体外阻断 PD-1 可使上述免疫表型几乎正常化并恢复 T 细胞功能,逆转观察到的 COVID-19 后免疫异常;事实上,我们还观察到 T 细胞对 SARS-CoV-2 肽的反应性增加。最后,在中和测定中,PD-1 阻断并未改变 T 细胞中和 SARS-CoV-2 刺突假病毒感染的能力。免疫检查点阻断可改善 COVID-19 后免疫异常并刺激抗 SARS-CoV-2 免疫反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5615/8783674/801685036f1e/jciinsight-6-146701-g033.jpg

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